Irbesartan: A New Angiotensin Receptor Blocker for Hypertension
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Bristol-meyers squibb has introduced irbesartan (Avapro), a new angiotensin II receptor blocker (ARB), for the treatment of hypertension. Irbesartan is the third ARB to be introduced in the United States, joining losartan (Cozaar, Merck) and valsartan (Diovan, Novartis). These agents specifically block the angiotensin II subtype 1 receptors.
ARBs have become popular antihypertensives because of their similarity to angiotensin converting enzyme inhibitors (ACE inhibitors) but lack of ACE-inhibitor associated cough and angioedema.
Irbesartan was discovered by Sanofi Pharmaceutical, Inc., and has been codeveloped with Bristol-Meyers Squibb.
Indications
Irbesartan is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Potential Advantages
Angiotensin II receptor blockers, as a class, have not been associated with cough or angioedema, which can be problematic with ACE inhibitors.1 Irbesartan has the longest elimination half-life of all the currently available ARBs11-15 hours compared to 6-9 hours for losartan and valsartan. Irbesartan also has the highest absolute bioavailability60-80% compared to a mean of 25% and 33% for valsartan and losartan, respectively.2-4 The clinical significance of these pharmacokinetic differences is not clear, as there are currently no published comparative trials between ARBs. Irbesartan may be administered without regard to meals, whereas food reduces the bioavailability of valsartan by 40-50%, although the manufacturer’s labeling indicates that valsartan may be taken with or without food.4
Potential Disadvantage
As with ACE inhibitors, ARBs are contraindicated in the second and third trimesters of pregnancy. Irbesartan appears to be well tolerated in placebo controlled trials. The following percentages indicate the incidence of the side effects higher than placebo: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), fatigue (4% vs 3%), musculoskeletal pain (2% vs 1%), and upper respiratory infection (9% vs 6%).2
Dosing Information
Irbesartan is supplied as 75 mg, 150 mg, and 300 mg tablets. The recommended initial dose is 150 mg once daily. If blood pressure control is inadequate, a low dose of a diuretic (e.g., hydrochlorothiazide) may be added. Patients may be titrated to a maximum dose of 300 mg once a day.2
Irbesartan appears to provide 24-hour blood pressure control at a daily dose of 150 mg.5 No dosage adjustment is required in elderly patients or in patients with renal or hepatic impairment.2 It may be administered without regard to food, and there are no known drug interactions.
Comments
Angiotensin II is substance that regulates blood pressure and plasma volume. Angiotensin II converting enzyme inhibitors block the formation of angiotensin II from angiotensin I by inhibiting angiotensin converting enzyme (the same enzyme that metabolizes bradykinin). Angiotensin II receptor blockers exert their effect by blocking AT1, one of the two major subtypes of angiotensin receptors. It appears that most, if not all, of the blood pressure effects are mediated by AT1.6 This receptor system may also be involved in restenosis after angioplasty, cardiac hypertrophy, heart failure, myocardial infarction, and ventricular remodeling.6 Study of ARBs in these areas are in progress.
Irbesartan is the third ARB to be marketed, with several more in the drug development pipeline (eprosartan [SmithKline Beecham], candesartan [Astra Merck]). Clinical trials indicate that a once-a-day dose of 150-300 mg of irbesartan provides trough (24 hours post-dose) decreases in systolic and diastolic blood pressure of 8-10/5-6 mmHg and 8-12/5-8 mmHg compared to placebo.2 Efficacy in treatment of blood pressure is similar to an ACE inhibitor such as enalapril.7 One study, published in abstract form, suggested that irbesartan 300 mg was more efficacious than losartan 100 mg.8
ARBs are also being studied in heart failure and diabetic nephropathy.
Clinical Implications
ARBs are effective alternatives to ACE inhibitors when ACE-inhibitor-induced cough or angioedema is suspected. Consider drug-induced cough if a dry, nonproductive cough begins soon after initiation of therapy with an ACE inhibitor. Before seeking other causes with various diagnostic tests, withdraw the drug for four days. If the cough improves, a rechallenge may be considered,9 or switching to an ARB or other antihypertensive may be appropriate.
Irbesartan appears to be at least as effective as other drugs in this class for the treatment of hypertension. The wholesale cost of irbesartan is $1.20 per day for the 150 mg tablet and $2.10 per day for the 300 mg tablets. The 150 mg tablet is priced similarly to losartan 25 mg and 50 mg, valsartan 80 mg and 160 mg, and enalapril 10 mg.
References
1. Goodfriend TL, et al. N Engl J Med 1996;334: 1649-1654.
2. Avapro Product Information. Bristol-Myers Squibb Company. October 1997.
3. Cozaar Product Information. Merck & Co. September 1995.
4. Diovan Product Information. Novartis.
5. Fogari R, et al. J Hypertens 1997;15 (Suppl 4) S113. Abstract.
6. Griendling KK, et al. Ann Rev Pharmacol Toxicol 1996;36:281-306.
7. Mimran A, et al J Hypertens 1997;15 (Suppl 4): S117. Abstract.
8. Gillis JC, et al. Drugs 1997;54:885-902.
9. Howard PA, et al. J Respir Dis 1997;18:762-768.
Gemfibrozil treatment of post-CABG patients with isolated low HDL has been associated with marked reduction in subsequent clinical events despite lack of any demonstrated angiographic benefit.
Which is not true about irbesartan?
a. The drug is contraindicated in pregnancy.
b. It has been shown to be effective for congestive heart failure and diabetic nephropathy.
c. It is dosed once a day.
d. The side effect profile is similar to placebo.
e. All of the above
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